T lymphocyte mediated immune responses are important in the development of most autoimmune diseases, including Type 1 insulin dependent diabetes mellitus (IDDM), and in transplant and tumour rejection in mammals (Slattery R M, Kjer-Nielsen L, Allison J, Charlton B, Mandel T E, Miller J F., "Prevention of diabetes in non-obese diabetic I-A.sup.K transgenic mice", Nature, (1990), vol. 345, pp. 724-6; Lund T, O'Reilly L, Hutchings P, et al., "Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain", Nature, (1990), vol. 345, pp. 727-9; Hutchings P R, Simpson E, O'Reilly L A, Lund T, Waldmann H, Cooke A., "The involvement of Ly2+T cells in beta cell destruction", J. Autoimmun. (1990), vol. 1, pp. 101-9).
Genetic components have been identified in several T cell mediated autoimmune diseases which heighten the risk of disease development. There is, however, strong evidence that non-genetic (environmentally acquired) agents or events also participate and trigger or sustain the autoimmune response. This has been shown, for example, in IDDM (Thorsby E, R.o slashed.nningen K S, "Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to Type 1 (insulin dependent) diabetes mellitus", Diabetologia, (1993), vol. 36, pp. 371-377).
There is at present no universally accepted model of autoimmunity, but mimicry models have received much attention. In these models, autoimmunity is perceived as an immunological cross-reaction between an auto- or self-antigen and a bona fide external antigen (Gray C, Matzinger P., "T cell memory is shortlived in the absence of antigen", J. Exp. Med. (1991), vol. 174, pp. 969-972; Beverly PCL, "Is T cell memory maintained by cross-reactive stimulation?", Immunol. Today, (1990), vol. 11, pp. 203-205). T cell sensitisation to self-antigens has been demonstrated in several diseases, including multiple sclerosis where sensitisation to myelin basic protein occurs, IDDM, ulcerative colitis, and arthritis. In IDDM, both mimicry antigen and disease-related self-antigen have been identified.
A conventional view of autoimmune diseases would suggest that administration of the autoantigen or self-antigen against which T cells are sensitised, or of analogues or fragments of the autoantigens, should cause T cell proliferation and exacerbation of the disease.
Lake et al. (Intl. Immunol. (1993), vol. 5, pp. 461-466) and Sloan-Lancaster et al. (Nature (1993), vol. 363, pp. 156-159) have reported on in vitro studies of anergy induction in activated T lymphocytes when the cells were exposed to analogues or high concentrations of an exogenous antigen or peptide to which the cells had previously been sensitised by experimental immunisation.
The present inventors are the first to demonstrate anergy induction in diabetes by a bona fide self-antigen. Using IDDM as a model, they have shown that under conditions in which the endogenous mimicry antigen has a fully stimulatory effect on activated T lymphocytes, the related autoantigen renders these cells anergic. Surprisingly, the anergenic effect was shown to be dominant, so that T lymphocyte can be rendered anergic by the self-antigen even in the presence of the fully stimulatory mimicry antigen.
The inventors have shown that development of IDDM can be prevented by treatment early in life with the self-antigen or fragments thereof. They have also demonstrated suppressed or delayed development of IDDM by immunisation with the mimicry antigen or fragments thereof.